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Dormant, disseminated tumor cells (DTCs) can persist for decades in secondary tissues before being reactivated to form tumors. The properties of the premetastatic niche can influence the DTC phenotype. To better understand how matrix properties of premetastatic niches influence DTC behavior, three hydrogel formulations are implemented to model a permissive niche and two nonpermissive niches. Poly(ethylene glycol) (PEG)‐based hydrogels with varying adhesivity ([RGDS]) and degradability ([N‐vinyl pyrrolidinone]) are implemented to mimic a permissive niche with high adhesivity and degradability and two nonpermissive niches, one with moderate adhesivity and degradability and one with no adhesivity and high degradability. The influence of matrix properties on estrogen receptor positive (ER⁺) breast cancer cells (MCF7s) is determined via a multimetric analysis. MCF7s cultured in the permissive niche adopted a growth state, while those in the nonpermissive niche with reduced adhesivity and degradability underwent tumor mass dormancy. Complete removal of adhesivity while maintaining high degradability induced single cell dormancy. The ability to mimic reactivation of dormant cells through a dynamic increase in [RGDS] is also demonstrated. This platform provides the capability of inducing growth, dormancy, and reactivation of ER⁺ breast cancer and can be useful in understanding how premetastatic niche properties influence cancer cell fate.

The role of hydrogel properties in regulating the phenotype of triple negative metastatic breast cancer is investigated using four cell lines: the MDA‐MB‐231 parental line and three organotropic sublines BoM‐1833 (bone‐tropic), LM2‐4175 (lung‐tropic), and BrM2a‐831 (brain‐tropic). Each line is encapsulated and cultured for 15 days in three poly(ethylene glycol) (PEG)‐based hydrogel formulations composed of proteolytically degradable PEG, integrin‐ligating RGDS, and the non‐degradable crosslinker N‐vinyl pyrrolidone. Dormancy‐associated metrics including viable cell density, proliferation, metabolism, apoptosis, chemoresistance, phosphorylated‐ERK and ‐p38, and morphological characteristics are quantified. A multimetric classification approach is implemented to categorize each hydrogel‐induced phenotype as: 1) growth, 2) balanced tumor dormancy, 3) balanced cellular dormancy, or 4) restricted survival, cellular dormancy. Hydrogels with high adhesivity and degradability promote growth. Hydrogels with no adhesivity, but high degradability, induce restricted survival, cellular dormancy in the parental line and balanced cellular dormancy in the organotropic lines. Hydrogels with reduced adhesivity and degradability induce balanced cellular dormancy in the parental and lung‐tropic lines and balanced tumor mass dormancy in bone‐ and brain‐tropic lines. The ability to induce escape from dormancy via dynamic incorporation of RGDS is also presented. These results demonstrate that ECM properties and organ‐tropism synergistically regulate cancer cell phenotype and dormancy.